WO2019023960A1 - Maille fonctionnalisée et appareil fluidique pour capturer des cellules ou des molécules en solution - Google Patents

Maille fonctionnalisée et appareil fluidique pour capturer des cellules ou des molécules en solution Download PDF

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Publication number
WO2019023960A1
WO2019023960A1 PCT/CN2017/095556 CN2017095556W WO2019023960A1 WO 2019023960 A1 WO2019023960 A1 WO 2019023960A1 CN 2017095556 W CN2017095556 W CN 2017095556W WO 2019023960 A1 WO2019023960 A1 WO 2019023960A1
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WO
WIPO (PCT)
Prior art keywords
mesh
cavity
functionalized
molecules
capturing
Prior art date
Application number
PCT/CN2017/095556
Other languages
English (en)
Inventor
Jing YAN
Jerome Charmet
Bauer Wolfgang-Andreas CHRISTIAN
Ziyi Yu
Yang Yang
Original Assignee
Suzhou Bofu Biomedical Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Suzhou Bofu Biomedical Limited filed Critical Suzhou Bofu Biomedical Limited
Priority to US16/625,620 priority Critical patent/US20200156073A1/en
Priority to EP17919854.4A priority patent/EP3662052A4/fr
Priority to PCT/CN2017/095556 priority patent/WO2019023960A1/fr
Publication of WO2019023960A1 publication Critical patent/WO2019023960A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
    • C12M47/04—Cell isolation or sorting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/02—Membranes; Filters
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0652—Sorting or classification of particles or molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0668—Trapping microscopic beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/12—Specific details about manufacturing devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/12—Specific details about materials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings

Definitions

  • the present invention relates to apparatus for capturing cells (e.g. circulating tumor cells) via molecules expressed by said cells or molecules in solution, in particular to a functionalized mesh and an apparatus comprising the functionalized mesh for capturing target cells via molecules expressed by said cells or molecules in solution.
  • cells e.g. circulating tumor cells
  • an apparatus comprising the functionalized mesh for capturing target cells via molecules expressed by said cells or molecules in solution.
  • Circulating tumor cells which are tumor cells in blood circulation, are considered as having a major relationship with issues such as distant metastasis of tumor.
  • CTCs Circulating tumor cells
  • Current bottlenecks hindering a rapid detection of cells from blood samples of patients are the low throughput and poor efficiency of capturing devices and methods.
  • the traditional magnetic activated cell sorting method has good reproducibility, high sensitivity and specificity, and is capable of analyzing CTCs quantitatively, however it is unfavorable because of its low operation speed and throughput.
  • the membrane microfiltration and the density gradient centrifugation technologies are simple to operate and enable the capture of cells, however it has low specificity and high false positive rate.
  • microfluidic devices Devices with functionalized posts or devices relying on separation techniques using acoustic, electrophoretic or centrifuge separation and filtration membranes have been used in microfluidic devices. Those devices are simple in operation and require fewer antibodies, but their cost and false negative rate are high and throughput low. Also, presently microfluidic technology companies are mainly focusing on research customers. The method requires mixing a variety of reagents in advance and is over-reliant on fabrication techniques that are not easily transferable to medium to large-scale manufacturing, thus the devices are difficult to industrialize and not easily applicable to in vitro diagnosis.
  • One purpose of the present invention is to provide a functionalized mesh for capturing target cells or molecules in solution, comprising a mesh substrate and a functional layer formed on said mesh substrate, wherein said functional layer comprises capturing substances that are specifically bindable with the target cells or molecules.
  • the functionalized mesh of the invention has high specificity, as well as high throughput and is suitable for capturing cells via molecules expressed by said cells or molecules in solution. It is particularly suited to capture and sort circulating tumor cells.
  • said molecules are proteins, oligonucleotides (DNA and/or RNA), enzymes or any combination thereof in solution or expressed by cells.
  • said capturing substances are selected from the group consisting of antibodies (including nanobodies), oligonuecleotides (including aptamer) and molecularly imprinted polymers.
  • said capturing substances are attached to said mesh substrate by physical adsorption and/or chemical bonding.
  • said chemical bonding is achieved by using thiolated molecules with or without a linker, using traut's reagent, silanisation or click chemistry.
  • said capturing substances are antibodies, which are attached to said mesh substrate by using traut's reagent or thiolated molecules with biotin-avidin.
  • said antibodies are anti-epithelial cell adhesion molecule antibodies, which can specifically bind with epithelial cell adhesion molecule expressed at the surface of circulating cancer cell.
  • said anti - epithelial cell adhesion molecule antibodies are attached to said mesh substrate by traut's reagent or thiolated molecules with biotin-avidin.
  • said mesh substrate is 2-10 mm ⁇ 2-10 mm in size and the opening of said mesh is 20 ⁇ m-100 ⁇ m.
  • the material of said mesh substrate is metal.
  • the metal is gold, stainless steel or their combination.
  • the mesh substrate comprises:
  • said surface coating is made of gold or other noble metal or alloy thereof (such as AuPd), and said capturing substances are attached to said surface coating.
  • said surface coating is deposited using magnetron sputtering or electrochemistry.
  • Another purpose of the present invention is to provide a fluidic apparatus for capturing cells or molecules in solution, comprising a capturing device, wherein said capturing device comprises at least one functionalized mesh as set forth above.
  • the apparatus of the invention has high specificity, as well as high throughput and is suitable for capturing cells via molecules expressed by said cells or molecules in solution. It is particularly suited to capture and sort circulating tumor cells.
  • said capturing device comprises one or multiple said functionalized mesh(es) stacked together.
  • said apparatus further comprises a body which has an inlet, a first outlet and a cavity located between said inlet and said first outlet, said capturing device is fixed inside said cavity, said inlet and said first outlet communicate with the cavity.
  • the body is fabricated using established manufacturing technique such as injection moulding.
  • the material of the body should also be compatible with solvents.
  • PEEK polyetheretherketone
  • said cavity is divided into two parts namely a first cavity and a second cavity by said capturing device.
  • Said mesh is horizontally disposed, said inlet is located above the capturing device and communicated with said first cavity; said first outlet is located below the capturing device and communicated with said second cavity.
  • the central lines of said inlet and said first outlet are perpendicular to the plane of said functionalized mesh.
  • said body further has a second outlet and a microfluidic channel communicated with said cavity and said second outlet for collection of captured cells or molecules is provided inside of said body.
  • said apparatus further comprises a counting device arranged in said microfluidic channel for counting captured cells or molecules.
  • said counting device comprises electrodes for impedance measurement.
  • said cavity is divided into two parts namely a first cavity and a second cavity by said capturing device, said inlet is communicated with said first cavity, said microfluidic channel is communicated with said second cavity.
  • Figure 1 is a schematic view of the apparatus for capturing CTCs according to the present invention.
  • Figure 2 is a schematic view of the functionalized mesh according to the present invention with captured CTCs.
  • Figure 3 is a section view of part of the functionalized mesh according to the present invention.
  • Figure 4a is a flow diagram of the method for capturing circulating tumor cells
  • Figure 4b shows a typical workflow of sorting circulating tumor cells by using the apparatus shown in figure 1.
  • Figure 5a and 5b are images showing two kinds of circulating tumor cells expressing target capture molecule captured on functionalized mesh.
  • 2 - capturing device 20 - mesh; 201 - stainless steel body; 202 - surface coating; 21 - antibodies;
  • the apparatus disclosed in the present invention relies on using one or more functionalized mesh(s) to capture circulating tumor cells (CTCs) in a hybrid macro/micro-fluidic device ( Figure1).
  • the 'macro' part is used to optimize the capture by increasing the capture area while minimizing the time of the assay.
  • the 'micro' part will be used to detect and collect the CTCs.
  • Figure 1 shows an exemplary embodiment of a fluidic apparatus for capturing CTCs.
  • the apparatus comprises:
  • a body 1 with a cavity 10 inside and having an inlet 11 and a first and second outlet 12 and 14;
  • a capturing device 2 comprising at least one functionalized mesh 20;
  • the body 1 is fabricated using established manufacturing technique such as injection moulding.
  • the material of the body should also be compatible with solvents.
  • PEEK polyetheretherketone
  • the body 1 is manufactured by injection moulding to form the cavity 10.
  • the capturing device 2 is arranged in the cavity 10.
  • the inlet 11 and the first outlet 12 are set at two ends of the cavity respectively and communicated with the cavity 10, and the capturing device 2 is located inside the cavity 10 and between the inlet 11 and the first outlet 12. More specifically, the inlet 11 is opened on the top surface of the body 1 and the first outlet 12 is opened on the bottom surface of the body 1, i.e. the inlet 11 is above the capturing device 2 and the first outlet 12 is below the capturing device 2.
  • the cavity 10 is divided into two parts namely the upper cavity 101 (the first cavity) and the lower cavity 102 (the second cavity) by the capturing device 2. Both the upper cavity 101 and the lower cavity 102 are cuboid and the cross section area along horizontal direction of the upper cavity 101 is larger than that of the lower cavity 102.
  • the functionalized mesh 20 of the capturing device 2 is prepared to have capturing substances that can specifically bind with target cells or molecules expressed by cells in solution or expressed at the surface of a cell membrane using any affinity base technique.
  • Target cells or molecules in medium especially solution e.g. unprocessed blood
  • target cells or molecules are captured by the capturing device 2 while other part of the blood goes through the capturing device 2 untrapped.
  • the advantage of the functionalized mesh is the high surface to volume ratio allowing the processing of large volume of samples while minimizing the risk of clogging.
  • the target cells or molecules Once the target cells or molecules have been captured, they can be released (e.g. chemically, thermally, electrically) for further analysis. Typically, the cells are counted and then collected for further analysis.
  • the mesh can captures any target cells or molecules and these molecules can either be 'floating' in a solution (biofluid or else) or attached to a cell (in this case, it will be capturing the cells).
  • the capturing device 2 may consists of multiple functionalized meshes stacked together.
  • antibodies 21 which can capture molecule on the surface of circulating cancer cell are attached to each mesh 20.
  • the antibodies 21 are anti - epithelial cell adhesion molecule (anti - EpCAM) antibodies.
  • the anti - epithelial cell adhesion molecule antibodies can bind with molecule, specifically, epithelial cell adhesion molecule (EpCAM), of circulating cancer cells, thus circulating cancer cells expressing can be captured.
  • EpCAM epithelial cell adhesion molecule
  • Material of the mesh 20 can be selected from gold or other noble metals and stainless steel coated with gold or other noble metals.
  • the functionalized mesh 20 comprises: a stainless steel body 201 and a surface coating 202 provided on the stainless steel body 201.
  • the material of the surface coating 202 is gold or gold alloy (e.g. AuPd), and the antibodies 21 are attached to the surface coating 202.
  • the surface coating 202 is AuPd coating deposited on the stainless steel body 201 by using magnetron sputtering or electrochemistry.
  • the anti - epithelial cell adhesion molecule antibodies are attached to the mesh 20 by traut's reagent, or thiolated biotin-avidin linker instead of traut's reagent.
  • a microfluidic channel 13 is also provided inside of the body 1, which is communicated with the lower cavity of the cavity 10 through which circulating cancer cells captured by the mesh 20 can be collected, after they are detached from the mesh 20 by cell detachment buffer.
  • the counting device 3 is arranged in the microfluidic channel 13 to count the numbers of captured circulating cancer cells.
  • the counting device 3 comprises electrodes 30 for impedance measurement.
  • the second outlet 14 opened on the top surface of the body 1 is communicated with the microfluidic channel 13 for captured circulating cancer cells flowing out of the body 1.
  • a method for capturing circulating cancer cells comprises steps of:
  • step of (I) inject the unprocessed blood in the cavity 10 though the inlet 11 via a pump; in the step of (II), pump down the unprocessed blood through the functionalized mesh 20 so that the CTCs bind to the functionalized mesh 20, reverse the operation of the pump to get the blood pass though the functionalized mesh 20 a couple of times to improve the bind efficiency, while the waste blood is flow out though the first outlet 12; in the step of (III), rinse the functionalized mesh 20 in water or other mild solvent to remove all unbound debris, cells or molecules through the first outlet 12; in the step of (IV), close the first outlet 12 and inject cell detachment buffer (e.g.
  • the mesh with antibodies is designed by the specific antibody technique.
  • the antibodies are used to screen to ensure a high sensitivity, specificity and cell activity.
  • combining the mesh with antibodies and microfluidic technology improves the specific surface area and thus increase the flux.
  • A). as there are significant differences in size of the circulating tumor cells and most of the blood cells, and the circulating tumor cells are easily deformed.
  • An array of at least one said mesh can separate CTCs and retains live cells for subsequent monitoring.
  • the anti-EnCAM antibodies are attached to the mesh to ensure a high specificity for cells captured.
  • the apparatus containing the mesh is used to increase the flux, reduce the amount of sample, and the single sample operation time will be reduced to 1/3 of the traditional magnetic beads method. Further, the channel of injection can be multipled to further reduce the average operating time.
  • the preparation method comprises:
  • the openings (such as, 64 ⁇ m or 40 ⁇ m) of the gold mesh are chosen so as to maximise the contact time with circulating cells while preventing the risk of clogging.
  • the size of the gold mesh used in the following test was 2 ⁇ 2 mm squares. Larger size is preferred considering manipulation.
  • a number of cleaning methods were used to prepare the mesh prior to functionalization, including autoclaving, oxygen plasma cleaning, and sonication in various solutions, including piranha solutions. If, for example, the best results for the 64 ⁇ m gold mesh consists of 15 minute sonication (US) in detergent, rinsing, 15 minutes sonication (US) in 70% ethanol solution, rinsing, 5 minutes high-purity water. Shorter times can also be expected with harsher solutions (e.g. Piranha).
  • reaction mixture i.e. antibody + PBS with EDTA
  • 2 ⁇ 50 ⁇ l 50 ⁇ l being the minimum volume to immerse a gold mesh of roughly 2 mm square.
  • Optimum reaction time was found to be 1 hour. The time can be shortened in appropriate conditions
  • Cell choice - cells having high expression level of the EpCAM protein (e.g., CaCo2 and MCF7 cells) were used.
  • the mesh was rinsed using ultra-pure water, incubated in ultra-pure water solution for 2 minutes and rinsed again prior to microscope inspection.
  • FIG. 5a shows CaCo2 cells expressing target capture molecule captured on functionalized mesh after 1 hour incubation
  • figure 5b shows MCF7 cells expressing target capture molecule captured on functionalized mesh after 1 hour incubation. It can be seen from figures 5a and 5b that a mass of CaCo2 and MCF7 cells were captured by the mesh due to the binding of EpCAM of cells and the anti-EpCAM antibodies on the mesh, while the mesh is not clogged. It should be noted that the apparatus and the method according to the present invention can be used to capture target molecules in solution of various concentration.
  • the functionalized mesh according to the present invention allows for high contact time with the cells in blood while minimizing the risk of clogging.
  • mesh of large surface area it is possible to process large amounts of sample (ml) in a few minutes.
  • the mesh can be functionalized separately from the rest of the apparatus, thus minimizing the dead volume and therefore the amount of antibodies used for its functionalization and also enabling the use of efficient, but harsh pre- functionalization cleaning steps.

Abstract

L'invention concerne une maille fonctionnalisée et un appareil fluidique pour capturer des cellules ou des molécules en solution. La maille fonctionnalisée comprend un substrat maillé et une couche fonctionnelle formée sur ledit substrat maillé, la couche fonctionnelle comprenant des substances de capture qui peuvent se lier de manière spécifique aux cellules ou molécules cibles. La maille et l'appareil de l'invention ont une spécificité élevée, ainsi qu'un débit élevé, et sont appropriés pour capturer des molécules en solution ou exprimées à la surface de membranes cellulaires. L'invention est particulièrement appropriée pour capturer et trier des cellules tumorales circulantes.
PCT/CN2017/095556 2017-08-02 2017-08-02 Maille fonctionnalisée et appareil fluidique pour capturer des cellules ou des molécules en solution WO2019023960A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US16/625,620 US20200156073A1 (en) 2017-08-02 2017-08-02 Functionalized mesh and fluidic apparatus for capturing cells or molecules in solution
EP17919854.4A EP3662052A4 (fr) 2017-08-02 2017-08-02 Maille fonctionnalisée et appareil fluidique pour capturer des cellules ou des molécules en solution
PCT/CN2017/095556 WO2019023960A1 (fr) 2017-08-02 2017-08-02 Maille fonctionnalisée et appareil fluidique pour capturer des cellules ou des molécules en solution

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2017/095556 WO2019023960A1 (fr) 2017-08-02 2017-08-02 Maille fonctionnalisée et appareil fluidique pour capturer des cellules ou des molécules en solution

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WO2019023960A1 true WO2019023960A1 (fr) 2019-02-07

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US (1) US20200156073A1 (fr)
EP (1) EP3662052A4 (fr)
WO (1) WO2019023960A1 (fr)

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